History

Fact Explanation
Introduction Familial hypocalciuric hypercalcemia is a benign hereditory condition which affecting the regulation of calcium metabolism. This is a rare condition and genetically transmitted as an autosomal-dominant disease with high penetrance. It is caused by an inactivation in a gene which encoding the calcium sensing receptor. This leads to life long hypocalciuric hypercalcaemia[1][2].
asymptomatic In Familial hypocalciuric hypercalcaemia the phenotype is usually normal and patients will experience unspecific physical discomfort or asymptomatic disease. They will no have other hypercalcaemic features of cognitive dysfunction, kidney stones and skeletal complications[1][2].
Central nervous system involved features suggestive of hypercalcaemia like Lethargy, fatigue, uneasiness, anxiety, personality changes and poor memory. In central nervous system calcium plays a major role in electrical impulse transmission. calcium irons in the synapses helps to transmit signals across the cleft from one neuronal cell to another. Normally there are calcium sensing receptors throughout the brain. They are helpful during the development for neuronal cell growth, migration and maturation[4]. As this condition is caused by an inactivation in a gene which encoding the calcium sensing receptor causing hypercalcaemia patients will present with Central nervous system involved features like Lethargy, fatigue, uneasiness, anxiety, personality changes and poor memory due to hyper excitability of neurones.
Muscle weakness/ soreness Calcium is an important electrolyte in muscle contraction by reaction with regulatory proteins, actin and myosin[3]. With hypercalcaemia there will be continuous muscle contraction causing muscle soreness and weakness.
Family history of similer condition In here there is a relationship with inactivating mutations in the CaSR gene. So there can be a positive family history of Familial hypocalciuric hypercalcaemia[2]. Relative can be either present with above mentioned symptoms or with an incidental finding of hypercalcaemia on blood investigations.
References
  1. LIETMAN SA, GERMAIN-LEE EL, LEVINE MA. Hypercalcemia in Children and Adolescents Curr Opin Pediatr [online] 2010 Aug, 22(4):508-515 [viewed 10 September 2014] Available from: doi:10.1097/MOP.0b013e32833b7c23
  2. RASMUSSEN AQ, JøRGENSEN NR, SCHWARZ P. Clinical and biochemical outcomes of cinacalcet treatment of familial hypocalciuric hypercalcemia: a case series J Med Case Reports [online] :564 [viewed 13 September 2014] Available from: doi:10.1186/1752-1947-5-564
  3. SZENT-GYöRGYI AG. Calcium regulation of muscle contraction. Biophys J [online] 1975 Jul, 15(7):707-723 [viewed 16 September 2014] Available from: doi:10.1016/S0006-3495(75)85849-8
  4. CUNNINGHAM SM, MIHARA S, HIGASHI H. Presynaptic calcium channels mediating synaptic transmission in submucosal neurones of the guinea-pig caecum J Physiol [online] 1998 Jun 1, 509(Pt 2):425-435 [viewed 16 September 2014] Available from: doi:10.1111/j.1469-7793.1998.425bn.x

Examination

Fact Explanation
No signs Most patients with Familial hypocalciuric hypercalcemia In Familial hypocalciuric hypercalcaemia the phenotype is usually normal and patients will experience unspecific physical discomfort or asymptomatic disease. So majority of they do not have any specific findings on physical examination[1][2].
Signs of hypercalcaemia involving nervous system like restlessness and poor memory . In central nervous system calcium plays a major role in electrical impulse transmission. calcium irons in the synapses helps to transmit signals across the cleft from one neuronal cell to another[4]. Normally there are calcium sensing receptors throughout the brain. They are helpful during the development for neuronal cell growth, migration and maturation. On examination some patients with familial hypocalciuric hypercalcaemia will be restless and they will have poor memory.
muscle weakness Calcium is an important electrolyte in muscle contraction by reaction with regulatory proteins, actin and myosin[3]. With hypercalcaemia there will be continuous muscle contraction causing muscle soreness and weakness. On examination of the musculoskeletal system, muscle power will be less than normal due to continuous muscle contraction following life long hypercalcaemia.
References
  1. LIETMAN SA, GERMAIN-LEE EL, LEVINE MA. Hypercalcemia in Children and Adolescents Curr Opin Pediatr [online] 2010 Aug, 22(4):508-515 [viewed 10 September 2014] Available from: doi:10.1097/MOP.0b013e32833b7c23
  2. RASMUSSEN AQ, JøRGENSEN NR, SCHWARZ P. Clinical and biochemical outcomes of cinacalcet treatment of familial hypocalciuric hypercalcemia: a case series J Med Case Reports [online] :564 [viewed 13 September 2014] Available from: doi:10.1186/1752-1947-5-564
  3. SZENT-GYöRGYI AG. Calcium regulation of muscle contraction. Biophys J [online] 1975 Jul, 15(7):707-723 [viewed 16 September 2014] Available from: doi:10.1016/S0006-3495(75)85849-8
  4. CUNNINGHAM SM, MIHARA S, HIGASHI H. Presynaptic calcium channels mediating synaptic transmission in submucosal neurones of the guinea-pig caecum J Physiol [online] 1998 Jun 1, 509(Pt 2):425-435 [viewed 16 September 2014] Available from: doi:10.1111/j.1469-7793.1998.425bn.x

Differential Diagnoses

Fact Explanation
primary hyperparathyroidism[1] Primary hyperparathyroidism is characterized by increased serum calcium level following excessive production of parathormone. majority of patients are asymptomatic while some may present with skeletal complications( reduced bone mineral density, osteoporosis) and renal complications( renal stones)[1][2].
hypercalcaemia of malignancy Primary cancers occur in bones or secondary metastases can be leads to hypercalcaemia following bone lysis. They will present with bone pain and various hypercalcaemic features[1][3][4].
Use of thiazide diuretics Mild to moderate hypercalcaemia can develop with thiazide diuretics and patients will present with hypercalcaemic features following intake of these drugs[1][5]
References
  1. CHRISTENSEN SE, NISSEN PH, VESTERGAARD P, MOSEKILDE L. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes [online] 2011 Dec, 18(6):359-70 [viewed 10 September 2014] Available from: doi:10.1097/MED.0b013e32834c3c7c
  2. CHOPRA P, MITRA S. Patients with Symptomatic Primary Hyperparathyroidism: An Anaesthetic Challenge Indian J Anaesth [online] 2009 Aug, 53(4):492-495 [viewed 13 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894492
  3. MUNDY GR. Hypercalcemia of malignancy revisited. J Clin Invest [online] 1988 Jul, 82(1):1-6 [viewed 13 September 2014] Available from: doi:10.1172/JCI113555
  4. MUNDY GR, IBBOTSON KJ, D'SOUZA SM. Tumor products and the hypercalcemia of malignancy. J Clin Invest [online] 1985 Aug, 76(2):391-394 [viewed 13 September 2014] Available from: doi:10.1172/JCI111984
  5. STRONG P, JEWELL S, RINKER J, HOCH D, CRAPO L. Thiazide therapy and severe hypercalcemia in a patient with hyperparathyroidism. West J Med [online] 1991 Mar, 154(3):338-340 [viewed 13 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1002768

Investigations - for Diagnosis

Fact Explanation
Serum ionized calcium and total calcium There will be elevation in both serum ionized calcium and serum total calcium level[2]
Urinary calcium excretion The contion is associated with low urine calcium excretion[1]
calcium/creatinine clearance ratio from a 24-h urine collection In all patients with calcium/creatinine clearance ratio of 0.020/less are then test for mutations in the CASR gene to identify presence of Familial hypocalciuric hypercalcaemia. The sensitivity of this test is 98%[3].
Immunoreactive Parathyroid hormone assay unsuppressed or elevated plasma parathyroid hormone[1] can be seen due to increased blood calcium levels. In here with inactivating mutation in the gene which encoding the calcium sensing receptor the normal function is loss causing decreased sensitivity to serum ionized calcium. To regulate this calcium imbalance, parathyroid hormone release will increase[2].
serum magnesium Serum magnesium level will also noted to be elevated[2].
Bone scan This is useful in assessing the skeletal system in these patients with hypercalcaemia[4].
Renal function tests typically normal renal function can be seen in this condition[1]
References
  1. CHRISTENSEN SE, NISSEN PH, VESTERGAARD P, MOSEKILDE L. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes [online] 2011 Dec, 18(6):359-70 [viewed 10 September 2014] Available from: doi:10.1097/MED.0b013e32834c3c7c
  2. RASMUSSEN AQ, JøRGENSEN NR, SCHWARZ P. Clinical and biochemical outcomes of cinacalcet treatment of familial hypocalciuric hypercalcemia: a case series J Med Case Reports [online] :564 [viewed 13 September 2014] Available from: doi:10.1186/1752-1947-5-564
  3. GLENDENNING P. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century Clin Biochem Rev [online] 2003 Feb, 24(1):27-30 [viewed 13 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1853330
  4. ALEXANDRE C, CHAPPARD D, RIFFAT G. Bone histomorphometric analysis in familial hypocalciuric hypercalcaemia. J Clin Pathol [online] 1983 Nov, 36(11):1319-1320 [viewed 13 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC498555

Investigations - Fitness for Management

Fact Explanation
Echocardiogram and ECG These test are useful to rule out any cardiac complications associated with hypercalcaemia. Thought these test will be normal in Familial hypocalciuric hypercalcaemia in other hypercalcaemic conditions there will be arrhythmia and congestive cardiac failure[1].
Renal function tests like serun creatinine, blood urea and serum electrolytes with X ray KUB As there will be renal stones progressing to renal failure with other hypercalcaemic conditions these tests also very useful. X ray KUB can be indicated only in clinically suspected cases[2].
CT scan, MRI, Chest X ray, mammogram These are useful in assessing the presence of any primary cancer which commonly causes secondary bone metasteses like thyroid, breast, lungs, renal and prostate[3].
References
  1. SYMONS C, FORTUNE F, GREENBAUM RA, DANDONA P. Cardiac hypertrophy, hypertrophic cardiomyopathy, and hyperparathyroidism--an association. Br Heart J [online] 1985 Nov, 54(5):539-542 [viewed 13 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC481943
  2. CRAVEN BL, PASSMAN C, ASSIMOS DG. Hypercalcemic States Associated With Nephrolithiasis Rev Urol [online] 2008, 10(3):218-226 [viewed 13 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556488
  3. HOCHHEGGER B, MARCHIORI E, SOARES SOUZA A JR, SOARES SOUZA L, PALERMO L. MRI and CT findings of metastatic pulmonary calcification Br J Radiol [online] 2012 Mar, 85(1011):e069-e072 [viewed 13 September 2014] Available from: doi:10.1259/bjr/53649455

Investigations - Followup

Fact Explanation
Serum ionized calcium and total calcium As there will be elevation in both serum ionized calcium and serum total calcium level[2] this test is useful during the follow up to assess the calcium status of the patient as well as treatments for medications[1].
Parathyroid hormone level In here unsuppressed or elevated plasma parathyroid hormone can be seen due to increased blood calcium levels. So during follow up parathyroid hormone will be useful in assessing the condition[2][1].
References
  1. RASMUSSEN AQ, JøRGENSEN NR, SCHWARZ P. Clinical and biochemical outcomes of cinacalcet treatment of familial hypocalciuric hypercalcemia: a case series J Med Case Reports [online] :564 [viewed 13 September 2014] Available from: doi:10.1186/1752-1947-5-564
  2. CHRISTENSEN SE, NISSEN PH, VESTERGAARD P, MOSEKILDE L. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes [online] 2011 Dec, 18(6):359-70 [viewed 10 September 2014] Available from: doi:10.1097/MED.0b013e32834c3c7c

Investigations - Screening/Staging

Fact Explanation
Genetic screening[1] As Familial hypocalciuric hypercalcemia is a benign hereditory condition which genetically transmitted as an autosomal-dominant disease with high penetrance. It is caused by an inactivation in a gene which encoding the calcium sensing receptor. Patients are usually asymptomatic and they can be identified with screening [1][2][3].
References
  1. CHRISTENSEN SE, NISSEN PH, VESTERGAARD P, MOSEKILDE L. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes [online] 2011 Dec, 18(6):359-70 [viewed 10 September 2014] Available from: doi:10.1097/MED.0b013e32834c3c7c
  2. LIETMAN SA, GERMAIN-LEE EL, LEVINE MA. Hypercalcemia in Children and Adolescents Curr Opin Pediatr [online] 2010 Aug, 22(4):508-515 [viewed 10 September 2014] Available from: doi:10.1097/MOP.0b013e32833b7c23
  3. HEATH H 3RD. Familial benign hypercalcemia--from clinical description to molecular genetics. West J Med [online] 1994 Jun, 160(6):554-561 [viewed 14 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1022558

Management - General Measures

Fact Explanation
Health education Educate the patient and family regarding the condition, symptoms, possible complications and genetic susceptibility of other family members[1][2].
References
  1. HEATH H 3RD. Familial benign hypercalcemia--from clinical description to molecular genetics. West J Med [online] 1994 Jun, 160(6):554-561 [viewed 14 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1022558
  2. LIETMAN SA, GERMAIN-LEE EL, LEVINE MA. Hypercalcemia in Children and Adolescents Curr Opin Pediatr [online] 2010 Aug, 22(4):508-515 [viewed 10 September 2014] Available from: doi:10.1097/MOP.0b013e32833b7c23

Management - Specific Treatments

Fact Explanation
No treatment is currently recommended As this is a asymptomatic/ mildly symptomatic disease despite of life long hypercalcaemia, no treatment is currently recommended other than screening for rare complications like severe neonatal primary hyperparathyroidism and pancreatitis[1][2]. Treatment with diuretics and bisphosphonate is not proven to be benefited in familial hypocalciuric hypercalcaemia.
Total parathyroidectomy This is some times proven to be benefited[3].
References
  1. CHRISTENSEN SE, NISSEN PH, VESTERGAARD P, MOSEKILDE L. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes [online] 2011 Dec, 18(6):359-70 [viewed 10 September 2014] Available from: doi:10.1097/MED.0b013e32834c3c7c
  2. AUWERX J, BRUNZELL J, BOUILLON R, DEMEDTS M. Familial hypocalciuric hypercalcaemia--familial benign hypercalcaemia: a review. Postgrad Med J [online] 1987 Oct, 63(744):835-840 [viewed 16 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2428623
  3. BAI M, PEARCE SH, KIFOR O, TRIVEDI S, STAUFFER UG, THAKKER RV, BROWN EM, STEINMANN B. In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia. J Clin Invest [online] 1997 Jan 1, 99(1):88-96 [viewed 16 September 2014] Available from: doi:10.1172/JCI119137